- Open Access
Growing pigs developed different types of diabetes induced by streptozotocin depending on their transcription factor 7-like 2 gene polymorphisms
Laboratory Animal Research volume 34, pages185–194(2018)
The different polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene promote variances in diabetes susceptibility in humans. We investigated whether these genotypes also promote differences in diabetic susceptibility in commercial pigs. Growing pigs (Landrace, both sex, 50–60 kg) with the C/C (n=4) and T/T (n=5) TCF7L2 genotypes were identified and intravenously injected with streptozotocin (STZ, 40 mg/kg) twice in weekly intervals, then a high-energy diet was offered. Oral glucose tolerance tests, blood analyses and the homeostasis model assessment-insulin resistance (HOMA-IR) index calculations were performed. The animals were sacrificed at the end of 12 weeks of treatment to reveal the pancreas histomorphometry. The results showed that all of the treated pigs grew normally despite exhibiting hyperglycemia at two weeks after the induction. The glycemic level of the fasting or postprandial pigs gradually returned to normal. The fasting insulin concentration was significantly decreased for the T/T carriers but not for the C/C carriers, and the resulting HOMA-IR index was significantly increased for the C/C genotype, indicating that the models of insulin dependence and resistance were respectively developed by T/T and C/C carriers. The histopathological results illustrated a significant reduction in the pancreas mass and insulin active sites, which suggested increased damage. The results obtained here could not be compared with previous studies because the TCF7L2 background has not been reported. Growing pigs may be an excellent model for diabetic in children if the animals are genetically pre-selected.
Liu Z, Hu W, He T, Dai Y, Hara H, Bottino R, Cooper DKC, Cai Z, Mou L. Pig-to-Primate Islet Xenotransplantation: Past, Present, and Future. Cell Transplant 2017; 26(6): 925–947.
American Diabetes Association. (2) Classification and diagnosis of diabetes. Diabetes Care 2015; 38 (Suppl 1): S8–S16.
Basile KJ, Guy VC, Schwartz S, Grant SF. Overlap of genetic susceptibility to type 1 diabetes, type 2 diabetes, and latent autoimmune diabetes in adults. Curr Diab Rep 2014; 14(11): 550.
Redondo MJ, Grant SF, Davis A, Greenbaum C; T1D Exchange Biobank. Dissecting heterogeneity in paediatric Type 1 diabetes: association of TCF7L2 rs7903146 TT and low-risk human leukocyte antigen (HLA) genotypes. Diabet Med 2017; 34(2): 286–290.
Jin T. Current Understanding on Role of the Wnt Signaling Pathway Effector TCF7L2 in Glucose Homeostasis. Endocr Rev 2016; 37(3): 254–277.
van der Kroef S, Noordam R, Deelen J, Akintola AA, Jansen SW, Postmus I, Wijsman CA, Beekman M, Mooijaart SP, Slagboom PE, van Heemst D. Association between the rs7903146 Polymorphism in the TCF7L2 Gene and Parameters Derived with Continuous Glucose Monitoring in Individuals without Diabetes. PLoS One 2016; 11(2): e0149992.
Lin PC, Lin WT, Yeh YH, Wung SF. Transcription Factor 7-Like 2 (TCF7L2) rs7903146 Polymorphism as a Risk Factor for Gestational Diabetes Mellitus: A Meta-Analysis. PLoS One 2016; 11(4): e0153044.
Koopmans SJ, Schuurman T. Considerations on pig models for appetite, metabolic syndrome and obese type 2 diabetes: From food intake to metabolic disease. Eur J Pharmacol 2015; 759: 231–239.
Hiridis S, Konstantinidis K, Menenakos E, Diamantis T, Papalois A, Zografos G. Preliminary Results of the Influence of Duodenojejunal Bypass in a Porcine Model of Streptozotocin-Induced Diabetes Mellitus. Obes Surg 2016; 26(4): 882–890.
Du ZQ, Fan B, Zhao X, Amoako R, Rothschild MF. Association analyses between type 2 diabetes genes and obesity traits in pigs. Obesity (Silver Spring) 2009; 17(2): 323–329.
Fan B, Lkhagvadorj S, Cai W, Young J, Smith RM, Dekkers JC, Huff-Lonergan E, Lonergan SM, Rothschild MF. Identification of genetic markers associated with residual feed intake and meat quality traits in the pig. Meat Sci 2010; 84(4): 645–650.
National Research Council. Nutrient requirements of swine, 11th ed. The National Academies Press, Washington, D.C., 2011; pp 208–238.
Liu Y, Wang Z, Yin W, Li Q, Cai M, Zhang C, Xiao J, Hou H, Li H, Zu X. Severe insulin resistance and moderate glomerulosclerosis in a minipig model induced by high-fat/high-sucrose/highcholesterol diet. Exp Anim 2007; 56(1): 11–20.
National Research Council. Guide for the care and use of laboratory animals, 8th ed. The National Academies Press, Washington, D.C., 2011; pp 41–76.
Sankari S. A practical method of taking blood samples from the pig. Acta Vet Scand 1983; 24(1): 133–134.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28(7): 412–419.
Stahl WR. Organ weights in primates and other mammals. Science 1965; 150(3699): 1039–1042.
Furman BL. Streptozotocin-Induced Diabetic Models in Mice and Rats. Curr Protoc Pharmacol 2015; 70: 1–20.
King A, Bowe J. Animal models for diabetes: Understanding the pathogenesis and finding new treatments. Biochem Pharmacol 2016; 99: 1–10.
Koopmans SJ, Mroz Z, Dekker R, Corbijn H, Ackermans M, Sauerwein H. Association of insulin resistance with hyperglycemia in streptozotocin-diabetic pigs: effects of metformin at isoenergetic feeding in a type 2-like diabetic pig model. Metabolism 2006; 55(7): 960–971.
Manell EA, Rydén A, Hedenqvist P, Jacobson M, Jensen-Waern M. Insulin treatment of streptozotocin-induced diabetes reestablishes the patterns in carbohydrate, fat and amino acid metabolisms in growing pigs. Lab Anim 2014; 48(3): 261–269.
Hara H, Lin YJ, Zhu X, Tai HC, Ezzelarab M, Balamurugan AN, Bottino R, Houser SL, Cooper DK. Safe induction of diabetes by high-dose streptozotocin in pigs. Pancreas 2008; 36(1): 31–38.
Huang YH, Lo LL, Liu SH, Yang TS. Age-related changes in semen quality characteristics and expectations of reproductive longevity in Duroc boars. Anim Sci J 2010; 81(4): 432–437.
Eskenazi B, Wyrobek AJ, Sloter E, Kidd SA, Moore L, Young S, Moore D. The association of age and semen quality in healthy men. Hum Reprod 2003; 18(2): 447–454.
Kelsey MM, Bjornstad P, McFann K, Nadeau K. Testosterone concentration and insulin sensitivity in young men with type 1 and type 2 diabetes. Pediatr Diabetes 2016; 17(3): 184–190.
Cheung KK, Luk AO, So WY, Ma RC, Kong AP, Chow FC, Chan JC. Testosterone level in men with type 2 diabetes mellitus and related metabolic effects: A review of current evidence. J Diabetes Investig 2015; 6(2): 112–123.
Alonso-Magdalena P, Ropero AB, García-Arévalo M, Soriano S, Quesada I, Muhammed SJ, Salehi A, Gustafsson JA, Nadal A. Antidiabetic actions of an estrogen receptor β selective agonist. Diabetes 2013; 62(6): 2015–2025.
Kautzky-Willer A, Harreiter J, Pacini G. Sex and Gender Differences in Risk, Pathophysiology and Complications of Type 2 Diabetes Mellitus. Endocr Rev 2016; 37(3): 278–316.
Reaven EP, Gold G, Reaven GM. Effect of age on glucosestimulated insulin release by the beta-cell of the rat. J Clin Invest 1979; 64(2): 591–599.
Dabelea D, Mayer-Davis EJ, Saydah S, Imperatore G, Linder B, Divers J, Bell R, Badaru A, Talton JW, Crume T, Liese AD, Merchant AT, Lawrence JM, Reynolds K, Dolan L, Liu LL, Hamman RF; SEARCH for Diabetes in Youth Study. Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA 2014; 311(17): 1778–1786.
Mayer-Davis EJ, Lawrence JM, Dabelea D, Divers J, Isom S, Dolan L, Imperatore G, Linder B, Marcovina S, Pettitt DJ, Pihoker C, Saydah S, Wagenknecht L; SEARCH for Diabetes in Youth Study. Incidence Trends of Type 1 and Type 2 Diabetes among Youths, 2002–2012. N Engl J Med 2017; 376(15): 1419–1429.
Takamoto I, Kubota N, Nakaya K, Kumagai K, Hashimoto S, Kubota T, Inoue M, Kajiwara E, Katsuyama H, Obata A, Sakurai Y, Iwamoto M, Kitamura T, Ueki K, Kadowaki T. TCF7L2 in mouse pancreatic beta cells plays a crucial role in glucose homeostasis by regulating beta cell mass. Diabetologia 2014; 57(3): 542–553.
Shu L, Zien K, Gutjahr G, Oberholzer J, Pattou F, Kerr- Conte J, Maedler K. TCF7L2 promotes beta cell regeneration in human and mouse pancreas. Diabetologia 2012; 55(12): 3296–3307.
Yang TS, Lin JH. Variation of heart size and its correlation with growth performance and vascular space in domestic pigs. Anim Sci 1997; 64(3): 523–528.
Yang T.S. Wild to domestic: body and organ size matter fitness in boars. In: Jenkins OP (ed) Advances in Zoology Research. Nova Science Publishers, Inc., NY, 2012; pp 187–200.
Cooper DK, Ekser B, Ramsoondar J, Phelps C, Ayares D. The role of genetically engineered pigs in xenotransplantation research. J Pathol 2016; 238(2): 288–299.
About this article
Cite this article
Tu, C., Hsu, C., Lee, M. et al. Growing pigs developed different types of diabetes induced by streptozotocin depending on their transcription factor 7-like 2 gene polymorphisms. Lab Anim Res 34, 185–194 (2018). https://doi.org/10.5625/lar.2018.34.4.185
- Diabetes mellitus
- growing pigs
- high-energy diet
- transcription factor 7-like 2 genotype